Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nonalcoholic fatty liver disease (NAFLD) is very common in the United States, and in some patients it may lead to cirrhosis, liver failure, and liver cancer. NAFLD encompasses a spectrum of liver injury, ranging from steatosis to steatohepatitis, advanced fibrosis, and cirrhosis. Nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD, histologically comprises steatosis, balloon degeneration, inflammation, and fibrosis in varying degrees. It is generally believed that simple steatosis is benign with minimal risk of progression, whereas NASH is progressive and can lead to cirrhosis. The commonly associated risk factors for NAFLD include obesity, hyperlipidemia, and diabetes mellitus. The pathogenesis of NAFLD and NASH is not fully known; however, current evidence suggests that insulin resistance and lipid peroxidation play a role in the pathogenesis of this condition. Currently, there are no proven effective therapies available for the treatment of NASH. Although there are numerous studies that have explored various treatments for NASH, these generally consist of small numbers of patients with suboptimal endpoints. Treatment strategies for NAFLD and NASH can be broadly divided into 1) treatment or control of underlying risk factors such as hyperlipidemia, diabetes mellitus, and obesity; and 2) specific pharmacologic therapy such as insulin sensitizers, antioxidants, or cytoprotective agents. Newer thiazolidinediones, such as rosiglitazone and pioglitazone, have shown promise in the treatment of NASH in pilot studies. However, these agents should not be used in clinical practice until their efficacy and safety are firmly established in larger studies. Despite encouraging initial studies, the recently completed multicenter, randomized, controlled trial failed to show any efficacy for ursodeoxycholic acid in the treatment of NASH. Other agents, such as vitamin E, betaine, probucol, and atorvastatin, have been explored as therapeutic agents for NASH. However, none of these studies have shown convincingly their utility in the treatment of NASH. Attempts to identify optimal therapy for patients with NASH are being vigorously pursued by the research community and important advances are expected within next several years. Until then, subjects should be advised to avoid alcohol, lose weight, and exercise regularly, and meticulous attention should be paid to the control of their risk factors such as diabetes and hyperlipidemia.
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PMID:Treatment of Nonalcoholic Fatty Liver Disease. 1458 34

Insulin-like growth factor-binding protein-1 (IGFBP-1) is one of six soluble binding proteins that regulate the actions of the insulin-like growth factors (IGFs). Liver is the major source of IGFBP-1 in non-pregnant humans. In normal physiology, IGFBP-1 transcription is potently inhibited by insulin and serum levels are limited by a rapid clearance rate. Elevated levels of IGFBP-1 in liver disease have been attributed to insulin resistance; however, the relationships between these analytes have not been defined. We studied insulin, proinsulin and IGFBP-1 in normal subjects (NL, N=47, 43+/-12 yr), cirrhosis (CIR, N=29, 54+/-14 yr), hepatocellular carcinoma (HCC, N=42, 61+/-11 yr), and other liver tumors (TUM, N=8, 60+/-17 yr). All three analytes were significantly increased in liver disease (mean+/-SEM; p-values relative to normals): IGFBP-1 (NL 24+/-4 ng/ml; CIR 235+/-53, p<0.0001; HCC 505+/-105, p<0.0001; TUM 118+/-36, p<0.0001), insulin (NL 72+/-4 pM; CIR 261+/-62, p<0.0002; HCC 180+/-25, p<0.0001; TUM 189+/-58, p<0.0001), proinsulin (NL 6.5+/-0.7 pM; CIR 36.8+/-7.7, p<0.0001; HCC 26.2+/-3.8, p<0.0001; TUM 32.1+/-9.7, p<0.0001). The ratio of proinsulin to insulin was also significantly elevated in liver disease. A typical curvilinear inverse relationship of insulin and IGFBP-1 was observed, but was shifted several fold higher for the liver disease groups. Our results demonstrate that insulin and proinsulin are elevated in liver disease. However, these elevations are paradoxically accompanied by elevated IGFBP-1 levels, indicating disruption of normal regulatory mechanisms. IGFBP-1 is postulated to play a dynamic role in metabolic substrate utilization via regulation of free IGF. Therefore, inappropriate elevation of IGFBP-1 could play an important role in the metabolic disturbances associated with liver disease.
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PMID:Elevated insulin, proinsulin and insulin-like growth factor-binding protein-1 in liver disease. 1462 64

The management of chronic viral hepatitis has changed significantly with the availability of effective antiviral agents. There is now a high probability that timely intervention can arrest development of cirrhosis, thereby preventing mortality from portal hypertension, liver failure and liver cancer. This two-part review discusses the implications of this new era of antiviral therapy for physicians. The present review is about chronic hepatitis C virus (HCV); a similar review that considers the treatment of hepatitis B virus will be published in a later issue of the Internal Medicine Journal. Chronic HCV infection is common, but fibrotic progression of liver disease is slow and variable; many infected persons never develop cirrhosis. Case selection for antiviral therapy is crucial. The most effective therapy is a pegylated (long-acting) interferon with ribavirin. Sustained viral response (SVR) (absent viraemia 6 months after completing treatment) can be obtained in 40-60% of individuals infected with genotype 1 and in approximately 67% with genotype 4 after 12 months of treatment. Response rates are higher (75-85%) with genotypes 2 and 3 after only 6 months of treatment. Late relapse is negligible after SVR. This viral cure reverses hepatic fibrosis, reduces the risk of liver failure and of hepato-cellular carcinoma. Combination therapy requires a supportive setting to minimize the impact of side-effects and maximize therapeutic effectiveness. Overall management of HCV-infected persons must also embrace measures to improve quality of life by preventing or dealing with psychosocial issues and advocating lifestyle changes to counter comorbidity from alcohol, central obesity and insulin resistance. These latter factors favour fibrotic disease progression, complications of cirrhosis (such as hepatocellular carcinoma) and development of type 2 diabetes mellitus, as well as eroding the chances of SVR with antiviral therapy.
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PMID:Management of chronic hepatitis C virus infection: a new era of disease control. 1522 94

Protein-energy malnutrition (PEM) is a prevalent observation in cirrhotic patients. In advanced cirrhotic patients with hepatic encephalopathy, dietary protein should be restricted to the low level of 0.5 g/kg/day. In such a strictly protein restricted diet, branched amino acid-enriched nutritious products should be prescribed to improve PEM. Avoidance of day-time or nocturnal fasting by frequent meals and late evening snacks is another recommendation for prevention of PEM. The n-3 polyunsaturated fatty acids (PUFA) modulate lymphocyte proliferation and eicosapetaenoic acid (EPA) up-regulates the metabolic action of insulin. The dietary n-6/n-3 PUFA ratio should be maintained between 2.8 and 3.2 in chronic liver disease. Oxidative stress is suggested as a trigger in the progression of chronic liver disease. Antioxidant vitamins; Vitamins A, E and C and carotenes may be useful to prevent the progression of chronic liver disease. Zinc depression occurs in advanced liver disease and it reduces taste and immune function. A goal of dietary management in chronic liver disease should be preventing PEM and blocking progression to hepatic cancer, and improving quality of life.
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PMID:Chronic hepatic disease and dietary instruction. 1560 46

Although the target of hepatitis C virus (HCV) infection is the liver, it has become progressively more evident that HCV can induce diseases in numerous organs. Recently, much attention has been drawn to metabolic disorders in HCV infection. Initially, hepatic steatosis and disturbances in lipid metabolism were found to be characteristic of HCV infection, and, subsequently, a correlation was noted between HCV infection and diabetes. It is now evident that HCV, by itself, can induce insulin resistance by way of disturbing the intracellular signaling pathway of insulin by the function of HCV core protein. Insulin resistance, caused by HCV infection, evolves to type 2 diabetes when superimposed on a high-fat diet and obesity. The fact that HCV infection induces insulin resistance by the virus itself may influence the progression of chronic hepatitis and open up novel therapeutic approaches. When hepatitis C is compared with nonalcoholic steatohepatitis (NASH), there are a number of similarities and several differences. From the metabolic aspect, hepatitis C resembles NASH in numerous features, such as the presence of steatosis, serum dyslipidemia, and oxidative stress in the liver, suggesting that hepatitis C is a steatohepatitis. In contrast, there are noticeable differences between hepatitis C and NASH, in that HCV modulates cellular gene expression and intracellular signal transduction, including the activation of mitogen-activated protein (MAP) kinase and transcription factor activator protein (AP)-1, while such details have not been noted for NASH. This difference may explain the markedly higher incidence of HCC development in chronic hepatitis C compared with that in NASH. HCV infection needs to be viewed not only as a liver disease but also as a metabolic disease, and this viewpoint could open up a novel way to the molecular understanding of the pathogenesis of hepatitis C, as a virus-associated steatohepatitis (VASH).
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PMID:Metabolic aspects of hepatitis C viral infection: steatohepatitis resembling but distinct from NASH. 1586 69

Nonalcoholic fatty liver disease (NAFLD) is becoming an increasing cause of chronic liver damage. The decision of start a medical treatment is based on the documented risk of progression to cirrhosis and liver cancer, when steatohepatitis (NASH) occurs. The therapy of this syndrome requires, as obviously, some considerations on the natural history of the condition, on the efficacy and safety of various therapeutic options, as well as on the costs. Treatment of patients with NAFLD has typically been focused on the management of associated conditions such as obesity, diabetes mellitus and hyperlipemia. Weight loss improves insulin sensitivity, and NASH may resolve with weight reduction. Insulin resistance seems to be the common denominator in many cases of NAFLD. Two classes of drugs have been shown to correct insulin resistance: biguanides (e.g., metformin) and thiazolidinediones (e.g., rosiglitazone and pioglitazone). The last two decades have witnessed a considerable progress in the understanding of the mechanisms respon-sible for the fibrogenic progression of chronic liver diseases. Several drugs believed to be hepatoprotective or antifibrotic agent as UDCA, betaine, vitamin E, lecithin, beta-carotene and selenium have been used in patients with NASH. Silybin is the main component of silymarin that is absorbed when linked whith a phytosome. This substance reduces in rats the lipid-peroxidation and the activaction of hepatic stellate cells. In humans, some non controlled data show that silybin is able to reduce insulin resistance, liver steatosis and plasma markers of liver fibrosis.
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PMID:The treatment of NAFLD. 1623 94

The extracellular domain of the tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) may function as a soluble cytokine to selectively kill various cancer cells without toxicity to most normal cells. We constructed a series of recombinant adeno-associated virus (AAV) vectors expressing the extracellular domain of human TRAIL fused with signal peptides of human insulin, interferon, human growth hormone, and serum albumin and designated them as AAV-ISN-T, AAV-IFN-T, AAV-HGH-T, and AAV-Alb-T, respectively. Transduction of human SMMC-7721 liver cancer cells with AAV-ISN-T led to higher levels of TRAIL(95-281) protein expression in the cell culture media and produced more apoptosis of the cells in vitro than those with AAV-IFN-T, AAV-HGH-T, and AAV-Alb-T. The therapeutic potential of AAV-ISN-T was then evaluated in a transplanted mouse model established by injection of human liver cancer SMMC-7721 cells subcutaneously. Subsequent oral or intraperitoneal administration of AAV-ISN-T resulted in a rapid, high level and long time expression of soluble TRAIL in the sera and livers of the animals, as well as effective suppression of tumor growth, with no toxicity to normal hepatocytes. These data strongly suggest that it is possible to increase soluble TRAIL expression to make full use of tumoricidal activity of TRAIL as a therapeutic strategy. In conclusion, we provide evidence that oral administration of AAV-TRAIL might be an important alternative route with practical significance for cancer gene therapy.
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PMID:Oral adeno-associated virus-sTRAIL gene therapy suppresses human hepatocellular carcinoma growth in mice. 1631 90

Protein kinase B (PKB or Akt) plays an essential role in the actions of insulin, cytokines, and growth factors, although the substrates for PKB that are relevant to many of its actions require identification. In this study, we have reported the identification of p122RhoGAP, a GTPase-activating protein selective for RhoA and rodent homologue of the tumor suppressor deleted in liver cancer (DLC1) as a novel insulin-stimulated phosphoprotein in primary rat adipocytes. We have demonstrated that Ser-322 is phosphorylated upon insulin stimulation of intact cells and that this site is directly phosphorylated in vitro by PKB and ribosomal S6 kinase, members of the AGC (protein kinases A, G, and C) family of insulin-stimulated protein kinases. Furthermore, expression of constitutively active mutants of PKB or mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) stimulates Ser-322 phosphorylation in intact cells, demonstrating that activation of the PKB or MEK pathway is sufficient for Ser-322 phosphorylation in vivo. Indeed, in primary adipocytes, insulin-stimulated Ser-322 phosphorylation was almost exclusively regulated by the phosphatidylinositol 3-kinase/PKB pathway, whereas in immortalized cells, insulin-stimulated phosphorylation was predominantly regulated by the MEK/extracellular signal-regulated kinase/ribosomal S6 kinase pathway, with the phosphatidylinositol 3-kinase/PKB pathway playing a minor role. These results demonstrate that p122RhoGAP Ser-322 acts as an integrator of signal transduction in a manner dependent on the cellular context.
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PMID:Identification of p122RhoGAP (deleted in liver cancer-1) Serine 322 as a substrate for protein kinase B and ribosomal S6 kinase in insulin-stimulated cells. 1633 27

The authors report a 36-year old man, who had hepatocellular carcinoma with lung metastasis and presented with coma from hypoglycemia. Serum insulin and c-peptide level were suppressed. Serum cortisol level was appropriately increased during the event. He needed glucose at least 3.65 mg/kg/min intravenously to maintain euglycemia. Cytoreduction of the tumor was not possible due to advanced stage disease. The patient had several episodes of morning hypoglycemia, despite having oral prednisolone 40 mg/day. However, glucose requirement was decreased after steroid usage. Normoglycemia was accomplished by adjunctive frequent high carbohydrate meal. Prednisolone was replaced to a lower dosage dexamethasone (2 mg/day). He did not have recurrent hypoglycemia as long as he had a midnight snack. Articles regarding hypoglycemia in HCC were extensively reviewed.
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PMID:Hepatocellular carcinoma with persistent hypoglycemia: successful treatment with corticosteroid and frequent high carbohydrate intake. 1651 97

Glycogen synthase kinase 3beta (GSK3beta) is a well-known marker and potential therapeutic target in non-insulin-dependent diabetes mellitus and Alzheimer's disease. Our recent demonstration that GSK3beta has a previously unrecognized role in colorectal cancer facilitates the development of a nonradioisotopic in vitro kinase assay (NRIKA) for detecting GSK3beta activity in gastrointestinal cancer cells. The NRIKA uses a sequential combination of immunoprecipitations to isolate GSK3beta in sample cells' lysates, and an in vitro kinase reaction that uses recombinant beta-catenin protein (substrate) and nonradioisotopic ATP, followed by immunoblotting to detect beta-catenin phosphorylated in serine 33, 37 and/or threonine 41 residues. The NRIKA detected higher expression of active GSK3beta in stomach, colon, pancreas and liver cancer cell lines than in human embryonic kidney cells (HEK293) considered nonneoplastic. Inhibition of cancer cell-derived GSK3beta activity by GSK3beta inhibitors (SB-216763, AR-A014418) was detected by the NRIKA. GSK3beta inhibition attenuated survival and proliferation and induced apoptosis in all types of cancer cells but not in HEK293. These findings supported the idea that the pathologic roles of GSK3beta are definite and common in various types of cancer. The NRIKA provides a basis for evolving a high-throughput tool for testing substances for GSK3beta inhibition, and for screening and identifying novel GSK3beta inhibitors with a view to discovering drugs for treatment of cancer as well as non-insulin-dependent diabetes mellitus and Alzheimer's disease.
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PMID:Detection of active fraction of glycogen synthase kinase 3beta in cancer cells by nonradioisotopic in vitro kinase assay. 1765 46


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